PROJECT SUMMARY/ABSTRACT It is estimated that greater than 1/3 of the population of the United States is obese. Obesity is coupled to the development of many chronic diseases, including type 2 diabetes (T2D), which is projected to afflict over half a billion adults worldwide by 2040. Obesity is a consequence of a disparity between energy intake and expenditure, and decreasing obesity requires a reduction in energy intake and/or an increase in energy expenditure. Aside from diet and exercise, therapeutic interventions for obesity include bariatric surgery and the use of drugs that decrease energy intake. There is intense interest in developing alternative pharmacotherapy for obesity based on increasing energy expenditure via activation of brown adipose tissue (BAT), or `beiging' of white adipose tissue (WAT). Our groups have a longstanding interest in the regulation and function of a family of enzymes known as histone deacetylases (HDACs). During the course of our investigations, we discovered that HDAC11 functions as a repressor of the thermogenic gene program in BAT, and prevents beiging of WAT. Furthermore, we found that HDAC11 is not actually a deacetylase, but instead functions as an efficient lysine defatty-acylase. Since HDAC11-deficient mice are healthy, and HDAC11 has a unique catalytic activity compared to other HDAC isoforms, we hypothesize that selective HDAC11 inhibitors will increase energy expenditure and thus provide an innovative therapy for the treatment of obesity and T2D. Three specific aims are designed to discover small molecules that selectively inhibit HDAC11 defatty-acylase activity.